Gene Validity Curation

ADAMTS13 - congenital thrombotic thrombocytopenic purpura

Gene: ADAMTS13 (HGNC:1366)
Classification - 03/25/2020
Disease: congenital thrombotic thrombocytopenic purpura (MONDO_0010122)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: ADAMTS13 was first reported in relation to autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura (TTP) in 2001 (Levy et al., PMID: 11586351). TTP is characterized by a deficiency of ADAMTS13 which may be congenital/familial due to inherited variants in the ADAMTS13 gene (also called Upshaw-Shulman syndrome) or acquired due to autoantibodies against ADAMTS13. ADAMTS13 cleaves ultra large von Willebrand Factor multimers into smaller multimers, rendering them less adhesive to platelets, preventing thrombosis. Genetic modifiers and environmental triggers are reported to play a role in the disease onset and severity. At least 175 ADAMTS13 variants, ranging from missense, in-frame indel to nonsense, frameshifts have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case level data (12 points): Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs 11586351, 17003922, 19055667, 12393505). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. The mechanism for disease is loss of function (PMID: 11586351, 28416507, 27505881). Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays (PMID: 12775718, 17003922). Many attempts at recapitulating the disease phenotype in mice have been made and was achieved with the injection of ultralarge VWF multimers as a trigger (PMID: 22529289). Rescue evidence in mouse is also available (PMID: 28254814, 22529289). In summary, ADAMTS13 is definitively associated with autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on March 25, 2020 (SOP Version 6).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 8
12
12
Levy GG et al. 2001 Oct 4 (PMID:11586351); Fujimura Y et al. 2009 Mar (PMID:19055667); Schneppenheim R et al. 2003 Mar 1 (PMID:12393505); Donadelli R et al. 2006 Oct (PMID:17003922);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
2
Donadelli R et al. 2006 Oct (PMID:17003922);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Dong JF et al. 2003 Aug 8 (PMID:12775718);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Donadelli R et al. 2006 Oct (PMID:17003922);
Models Non-human model organism 2 0 - 4 4 1 2 4
Schiviz A et al. 2012 Jun 21 (PMID:22529289);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 2
2.5
Schiviz A et al. 2012 Jun 21 (PMID:22529289); Verhenne S et al. 2017 May (PMID:28254814);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
03/26/2020
EXPERT CURATION (DATE)
Definitive
03/25/2020
EVIDENCE SUMMARY
ADAMTS13 was first reported in relation to autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura (TTP) in 2001 (Levy et al., PMID: 11586351). TTP is characterized by a deficiency of ADAMTS13 which may be congenital/familial due to inherited variants in the ADAMTS13 gene (also called Upshaw-Shulman syndrome) or acquired due to autoantibodies against ADAMTS13. ADAMTS13 cleaves ultra large von Willebrand Factor multimers into smaller multimers, rendering them less adhesive to platelets, preventing thrombosis. Genetic modifiers and environmental triggers are reported to play a role in the disease onset and severity. At least 175 ADAMTS13 variants, ranging from missense, in-frame indel to nonsense, frameshifts have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of case level data (12 points): Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs 11586351, 17003922, 19055667, 12393505). More evidence is available in the literature, but the maximum score for genetic evidence evidence (12 pts) has been reached. The mechanism for disease is loss of function (PMID: 11586351, 28416507, 27505881). Summary of experimental data (5 points): This gene-disease relationship is supported by animal models and in vitro functional assays (PMID: 12775718, 17003922). Many attempts at recapitulating the disease phenotype in mice have been made and was achieved with the injection of ultralarge VWF multimers as a trigger (PMID: 22529289). Rescue evidence in mouse is also available (PMID: 28254814, 22529289). In summary, ADAMTS13 is definitively associated with autosomal recessive Congenital Thrombotic Thrombocytopenic Purpura. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on March 25, 2020 (SOP Version 6).